Abstract
Post-stroke secondary brain damage is significantly influenced by the induction and accumulation of α-Synuclein (α-Syn). α-Syn-positive inclusions are often present in tauopathies and elevated tau levels and phosphorylation promotes neurodegeneration. Glycogen synthase kinase 3β (GSK-3β) is a known promoter of tau phosphorylation. We currently evaluated the interaction of α-Syn with GSK-3β and tau in post-ischemic mouse brain. Transient focal ischemia led to increased cerebral protein–protein interaction of α-Syn with both GSK-3β and tau and elevated tau phosphorylation. Treatment with a GSK-3β inhibitor prevented post-ischemic tau phosphorylation. Furthermore, α-Syn interaction was observed to be crucial for post-ischemic GSK-3β-dependent tau hyperphosphorylation as it was not seen in α-Syn knockout mice. Moreover, tau knockout mice show significantly smaller brain damage after transient focal ischemia. Overall, the present study indicates that GSK-3β catalyzes the α-Syn-dependent tau phosphorylation and preventing this interaction is crucial to limit post-ischemic secondary brain damage.
Similar content being viewed by others
Data Availability
All data needed to evaluate the conclusions in the paper are present in the main document.
References
Ballatore, C., Lee, V. M., & Trojanowski, J. Q. (2007). Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nature Reviews Neuroscience, 8(9), 663–672. https://doi.org/10.1038/nrn2194
Bi, M., Gladbach, A., van Eersel, J., Ittner, A., Przybyla, M., van Hummel, A., Chua, S. W., van der Hoven, J., Lee, W. S., Müller, J., Parmar, J., Jonquieres, G. V., Stefen, H., Guccione, E., Fath, T., Housley, G. D., Klugmann, M., Ke, Y. D., & Ittner, L. M. (2017). Tau exacerbates excitotoxic brain damage in an animal model of stroke. Nature Communications, 8(1), 473. https://doi.org/10.1038/s41467-017-00618-0
Chelluboina, B., Chokkalla, A. K., Mehta, S. L., Morris-Blanco, K. C., Bathula, S., Sankar, S., Park, J. S., & Vemuganti, R. (2021). Tenascin-C induction exacerbates post-stroke brain damage. Journal of Cerebral Blood Flow and Metabolism. https://doi.org/10.1177/0271678x211056392
Chen, X., & Jiang, H. (2019). Tau as a potential therapeutic target for ischemic stroke. Aging (albany NY), 11(24), 12827–12843. https://doi.org/10.18632/aging.102547
Chokkalla, A. K., Mehta, S. L., Kim, T., Chelluboina, B., Kim, J., & Vemuganti, R. (2019). Transient focal ischemia significantly alters the m(6)A epitranscriptomic tagging of RNAs in the brain. Stroke, 50(10), 2912–2921. https://doi.org/10.1161/strokeaha.119.026433
Clinton, L. K., Blurton-Jones, M., Myczek, K., Trojanowski, J. Q., & LaFerla, F. M. (2010). Synergistic Interactions between Abeta, tau, and alpha-synuclein: Acceleration of neuropathology and cognitive decline. Journal of Neuroscience, 30(21), 7281–7289. https://doi.org/10.1523/jneurosci.0490-10.2010
Credle, J. J., George, J. L., Wills, J., Duka, V., Shah, K., Lee, Y. C., Rodriguez, O., Simkins, T., Winter, M., Moechars, D., Steckler, T., Goudreau, J., Finkelstein, D. I., & Sidhu, A. (2015). GSK-3β dysregulation contributes to parkinson’s-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein. Cell Death and Differentiation, 22(5), 838–851. https://doi.org/10.1038/cdd.2014.179
Duka, T., Duka, V., Joyce, J. N., & Sidhu, A. (2009). Alpha-Synuclein contributes to GSK-3beta-catalyzed Tau phosphorylation in Parkinson’s disease models. The FASEB Journal, 23(9), 2820–2830. https://doi.org/10.1096/fj.08-120410
Duka, T., Rusnak, M., Drolet, R. E., Duka, V., Wersinger, C., Goudreau, J. L., & Sidhu, A. (2006). Alpha-synuclein induces hyperphosphorylation of Tau in the MPTP model of parkinsonism. FASEB Journal, 20(13), 2302–2312. https://doi.org/10.1096/fj.06-6092com
Farr, S. A., Ripley, J. L., Sultana, R., Zhang, Z., Niehoff, M. L., Platt, T. L., Murphy, M. P., Morley, J. E., Kumar, V., & Butterfield, D. A. (2014). Antisense oligonucleotide against GSK-3β in brain of SAMP8 mice improves learning and memory and decreases oxidative stress: Involvement of transcription factor Nrf2 and implications for Alzheimer disease. Free Radical Biology and Medicine, 67, 387–395. https://doi.org/10.1016/j.freeradbiomed.2013.11.014
Forman, M. S., Schmidt, M. L., Kasturi, S., Perl, D. P., Lee, V. M., & Trojanowski, J. Q. (2002). Tau and alpha-synuclein pathology in amygdala of Parkinsonism-dementia complex patients of Guam. American Journal of Pathology, 160(5), 1725–1731. https://doi.org/10.1016/s0002-9440(10)61119-4
Galpern, W. R., & Lang, A. E. (2006). Interface between tauopathies and synucleinopathies: A tale of two proteins. Annals of Neurology, 59(3), 449–458. https://doi.org/10.1002/ana.20819
Gonçalves, R. A., Wijesekara, N., Fraser, P. E., & De Felice, F. G. (2020). Behavioral abnormalities in knockout and humanized tau mice. Front Endocrinol (lausanne), 11, 124. https://doi.org/10.3389/fendo.2020.00124
Gordon-Krajcer, W., Kozniewska, E., Lazarewicz, J. W., & Ksiezak-Reding, H. (2007). Differential changes in phosphorylation of tau at PHF-1 and 12E8 epitopes during brain ischemia and reperfusion in gerbils. Neurochemical Research, 32(4–5), 729–737. https://doi.org/10.1007/s11064-006-9199-3
Guo, T., Noble, W., & Hanger, D. P. (2017). Roles of tau protein in health and disease. Acta Neuropathologica, 133(5), 665–704. https://doi.org/10.1007/s00401-017-1707-9
Kim, T., Chokkalla, A. K., & Vemuganti, R. (2021). Deletion of ubiquitin ligase Nedd4l exacerbates ischemic brain damage. Journal of Cerebral Blood Flow and Metabolism, 41(5), 1058–1066. https://doi.org/10.1177/0271678x20943804
Kim, T., Mehta, S. L., Kaimal, B., Lyons, K., Dempsey, R. J., & Vemuganti, R. (2016). Poststroke Induction of alpha-synuclein mediates ischemic brain damage. Journal of Neuroscience, 36(26), 7055–7065. https://doi.org/10.1523/jneurosci.1241-16.2016
Kim, T., Mehta, S. L., Morris-Blanco, K. C., Chokkalla, A. K., Chelluboina, B., Lopez, M., Sullivan, R., Kim, H. T., Cook, T. D., Kim, J. Y., Kim, H., Kim, C., & Vemuganti, R. (2018). The microRNA miR-7a-5p ameliorates ischemic brain damage by repressing alpha-synuclein. Sci Signal. https://doi.org/10.1126/scisignal.aat4285
Lashuel, H. A., Overk, C. R., Oueslati, A., & Masliah, E. (2013). The many faces of α-synuclein: From structure and toxicity to therapeutic target. Nature Reviews Neuroscience, 14(1), 38–48. https://doi.org/10.1038/nrn3406
Lei, P., Ayton, S., Bush, A. I., & Adlard, P. A. (2011). GSK-3 in Neurodegenerative Diseases. Int J Alzheimers Dis, 2011, 189246. https://doi.org/10.4061/2011/189246
Mehta, S. L., Chokkalla, A. K., Bathula, S., & Vemuganti, R. (2022). MicroRNA miR-7 Is Essential for Post-stroke Functional Recovery. Translational Stroke Research. https://doi.org/10.1007/s12975-021-00981-7
Mehta, S. L., Kim, T., & Vemuganti, R. (2015). Long Noncoding RNA FosDT Promotes Ischemic Brain Injury by Interacting with REST-Associated Chromatin-Modifying Proteins. Journal of Neuroscience, 35(50), 16443–16449. https://doi.org/10.1523/jneurosci.2943-15.2015
Mehta, S. L., Pandi, G., & Vemuganti, R. (2017). Circular RNA expression profiles alter significantly in mouse brain after transient focal ischemia. Stroke, 48(9), 2541–2548. https://doi.org/10.1161/strokeaha.117.017469
Mondragón-Rodríguez, S., Perry, G., Luna-Muñoz, J., Acevedo-Aquino, M. C., & Williams, S. (2014). Phosphorylation of tau protein at sites Ser(396–404) is one of the earliest events in Alzheimer’s disease and Down syndrome. Neuropathology and Applied Neurobiology, 40(2), 121–135. https://doi.org/10.1111/nan.12084
Morfini, G., Szebenyi, G., Elluru, R., Ratner, N., & Brady, S. T. (2002). Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin-based motility. EMBO Journal, 21(3), 281–293. https://doi.org/10.1093/emboj/21.3.281
Morioka, M., Kawano, T., Yano, S., Kai, Y., Tsuiki, H., Yoshinaga, Y., Matsumoto, J., Maeda, T., Hamada, J., Yamamoto, H., Fukunaga, K., & Kuratsu, J. (2006). Hyperphosphorylation at serine 199/202 of tau factor in the gerbil hippocampus after transient forebrain ischemia. Biochemical and Biophysical Research Communications, 347(1), 273–278. https://doi.org/10.1016/j.bbrc.2006.06.096
Moussaud, S., Jones, D. R., Moussaud-Lamodière, E. L., Delenclos, M., Ross, O. A., & McLean, P. J. (2014). Alpha-synuclein and tau: Teammates in neurodegeneration? Molecular Neurodegeneration, 9, 43. https://doi.org/10.1186/1750-1326-9-43
Percie du Sert, N., Hurst, V., Ahluwalia, A., Alam, S., Avey, M. T., Baker, M., Browne, W. J., Clark, A., Cuthill, I. C., Dirnagl, U., Emerson, M., Garner, P., Holgate, S. T., Howells, D. W., Karp, N. A., Lazic, S. E., Lidster, K., MacCallum, C. J., Macleod, M., Pearl, E. J., Petersen, O. H., Rawle, F., Reynolds, P., Rooney, K., Sena, E. S., Silberberg, S. D., Steckler, T., & Würbel, H. (2020). The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. PLoS Biology, 18(7), e3000410. https://doi.org/10.1371/journal.pbio.3000410
Pluta, R., Ułamek-Kozioł, M., Januszewski, S., & Czuczwar, S. J. (2018). Tau Protein Dysfunction after Brain Ischemia. Journal of Alzheimer’s Disease, 66(2), 429–437. https://doi.org/10.3233/jad-180772
Postina, R. (2008). A closer look at alpha-secretase. Current Alzheimer Research, 5(2), 179–186. https://doi.org/10.2174/156720508783954668
Roberson, E. D., Scearce-Levie, K., Palop, J. J., Yan, F., Cheng, I. H., Wu, T., Gerstein, H., Yu, G. Q., & Mucke, L. (2007). Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science, 316(5825), 750–754. https://doi.org/10.1126/science.1141736
Savica, R., Grossardt, B. R., Bower, J. H., Ahlskog, J. E., & Rocca, W. A. (2013). Incidence and pathology of synucleinopathies and tauopathies related to parkinsonism. JAMA Neurology, 70(7), 859–866. https://doi.org/10.1001/jamaneurol.2013.114
Toral-Rios, D., Pichardo-Rojas, P. S., Alonso-Vanegas, M., & Campos-Peña, V. (2020). GSK3β and Tau Protein in Alzheimer’s Disease and Epilepsy. Frontiers in Cellular Neuroscience, 14, 19. https://doi.org/10.3389/fncel.2020.00019
Torres, A. K., Jara, C., Olesen, M. A., & Tapia-Rojas, C. (2021). Pathologically phosphorylated tau at S396/404 (PHF-1) is accumulated inside of hippocampal synaptic mitochondria of aged Wild-type mice. Science and Reports, 11(1), 4448. https://doi.org/10.1038/s41598-021-83910-w
Unal-Cevik, I., Gursoy-Ozdemir, Y., Yemisci, M., Lule, S., Gurer, G., Can, A., Müller, V., Kahle, P. J., & Dalkara, T. (2011). Alpha-synuclein aggregation induced by brief ischemia negatively impacts neuronal survival in vivo: a study in [A30P]alpha-synuclein transgenic mouse. Journal of Cerebral Blood Flow & Metabolism, 31(3), 913–923. https://doi.org/10.1038/jcbfm.2010.170
Velazquez, R., Ferreira, E., Tran, A., Turner, E. C., Belfiore, R., Branca, C., & Oddo, S. (2018). Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits. Aging Cell, 17(4), e12775. https://doi.org/10.1111/acel.12775
Venna, V. R., Benashski, S. E., Chauhan, A., & McCullough, L. D. (2015). Inhibition of glycogen synthase kinase-3β enhances cognitive recovery after stroke: The role of TAK1. Learning & Memory, 22(7), 336–343. https://doi.org/10.1101/lm.038083.115
Wang, W., Li, M., Wang, Y., Li, Q., Deng, G., Wan, J., Yang, Q., Chen, Q., & Wang, J. (2016). GSK-3β inhibitor TWS119 attenuates rtPA-induced hemorrhagic transformation and activates the Wnt/β-catenin signaling pathway after acute ischemic stroke in rats. Molecular Neurobiology, 53(10), 7028–7036. https://doi.org/10.1007/s12035-015-9607-2
Wang, W., Li, M., Wang, Y., Wang, Z., Zhang, W., Guan, F., Chen, Q., & Wang, J. (2017). GSK-3β as a target for protection against transient cerebral ischemia. International Journal of Medical Science, 14(4), 333–339. https://doi.org/10.7150/ijms.17514
Wen, Y., Yang, S. H., Liu, R., Perez, E. J., Brun-Zinkernagel, A. M., Koulen, P., & Simpkins, J. W. (2007). Cdk5 is involved in NFT-like tauopathy induced by transient cerebral ischemia in female rats. Biochimica Et Biophysica Acta, 1772(4), 473–483. https://doi.org/10.1016/j.bbadis.2006.10.011
Zhou, Q., Li, S., Li, M., Ke, D., Wang, Q., Yang, Y., Liu, G. P., Wang, X. C., Liu, E., & Wang, J. Z. (2022). Human tau accumulation promotes glycogen synthase kinase-3β acetylation and thus upregulates the kinase: A vicious cycle in Alzheimer neurodegeneration. eBioMedicine, 78, 103970. https://doi.org/10.1016/j.ebiom.2022.103970
Acknowledgements
Partially supported by NIH RO1 NS101960 and UW Department of Neurological Surgery. Dr. Vemuganti is the recipient of a Research Career Scientist award (# IK6BX005690) from the US Department of Veterans Affairs. We thank Mr. Shreyas Kumar for proofreading the text.
Funding
National Institutes of Health, RO1 NS101960
Author information
Authors and Affiliations
Contributions
SLM, THK, BC, and RV contributed to the conception and design of the study; SLM, THK, and BC contributed to the acquisition and analysis of data; SLM, BC, and RV contributed to drafting the text.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Mehta, S.L., Kim, T., Chelluboina, B. et al. Tau and GSK-3β are Critical Contributors to α-Synuclein-Mediated Post-Stroke Brain Damage. Neuromol Med 25, 94–101 (2023). https://doi.org/10.1007/s12017-022-08731-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12017-022-08731-0